Process for preparing cinacalcet and pharmaceutically acceptable salts thereof

ABSTRACT

The present patent application relates to a process for preparing cinacalcet or a pharmaceutically acceptable salt thereof, which comprises reacting 3-trifluoromethylbenzaldehyde having the following formula (II) with the phosphorus-comprising derivative having the following formula (III) in which R 1  and R 2 , which may be identical or different, are each a (C 1 -C 6 )alkyl group. The present invention also relates to the phosphorus-comprising derivative having the formula (III), to the use thereof and to the process for preparing same. The present invention also relates to the phosphate salt of cinacalcet and to uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation Application of U.S. patentapplication Ser. No. 14/425,905, filed on Mar. 4, 2015, now U.S. Pat.No. 9,290,439, issued on Mar. 22, 2016, which is a U.S. National StageApplication pursuant to 35 U.S.C. §371 of International PatentApplication PCT/EP2013/068617, filed on Sep. 9, 2013, and published asWO 2014/037563 on Mar. 13, 2014, which claims priority to French PatentApplication 1258408, filed on Sep. 7, 2012, all of which areincorporated herein by reference in their entireties for all purposes.

The present invention relates to a process for preparing cinacalcet((R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]-propyl]-1-naphthalenemethanamine)or one of the pharmaceutically acceptable salts thereof which makesparticular use of diethyl ((R)-1-(1-naphthyl)ethylamino)vinylphosphonateas synthesis intermediate.

Cinacalcet is a calcimimetic active ingredient used in the treatment ofhyperparathyroidism and is marketed in particular under the preparatoryname Sensipar®.

Cinacalcet was described for the first time in 2006 in U.S. Pat. No.6,211,244. Although a process for the preparation of cinacalcet is notdescribed in this patent, similar compounds have been prepared byreaction between an amine and an aldehyde followed by reduction of theobtained imine in the presence of a cyanoborohydride.

Methods for preparing cinacalcet, analogue compounds and thepharmaceutically acceptable salts thereof have been described in U.S.Pat. No. 6,211,244, U.S. Pat. No. 7,250,533, U.S. Pat. No. 5,648,541,U.S. Pat. No. 7,247,751, U.S. Pat. No. 7,393,967, WO 06/125026, WO06/127933, WO 06/127941, WO 07/062147, WO 07/112280, WO 07/127445, WO07/127449, WO 08/058235, WO 08/000423, WO 08/035212, WO 08/058236, WO08/06862, WO 2009153814, WO 2010067204, WO 2010015935, WO 2010049293, WO2010103531, WO 2010128388, WO 2011050499.

WO 2009/153814 describes a process for preparing cinacalcet inaccordance with the following reaction scheme:

In this process, an unsaturated imine prepared from(R)-(+)-1-(1-naphthyl)ethylamine and3-[3-(trifluoromethyl)phenyl]propenaldehyde, is converted to unsaturatedcinacalcet in free from, which is then reduced by hydrogenationcatalysed by palladium and the cinacalcet in free from is converted tocinacalcet hydrochloride with gaseous hydrochloric acid.

WO 2010/015935 describes another process for preparing cinacalcet inaccordance with the following reaction scheme:

wherein: a. NaBH₄, methanol, b. HCl, acetonitrile/oxalic acid,acetonitrile/di-p-toluoyl-L-tartaric acid, methanol, c. (1) NaOH, water(2) HCl, acetonitrile, d. (1) Na₂CO₃, water, EtOAc (2) Pd(OH)₂, H₂ (3)NaHCO₃, di-tert-butyl dicarbonate, water, tetrahydrofuran (4) HCl,methanol.

The synthesis processes described in WO 2009/153814 and WO 2010/015935have the drawbacks of using borohydrides which are toxic, and ofrequiring complicated reaction sequences to purify the cinacalcet.

In addition, most of these processes require the use of complexintermediates and of reagents which are not commercially available andmust be previously synthesised. These processes are therefore notadapted for industrial application.

There is therefore a true need for the development of a novel route forsynthesising cinacalcet which does not have the disadvantages of priorart methods.

The inventors have consequently developed a novel process forsynthesising cinacalcet allowing for shorter synthesis and which ishence more economical and gives better performance.

The present invention therefore concerns a process for preparingcinacalcet of following formula (I):

or one of the pharmaceutically acceptable salts thereof, comprising thereaction of 3-(trifluoromethyl)benzaldehyde of following formula (II):

with the phosphorus-containing derivative of following formula (III):

where R₁ and R₂, the same or different, preferably the same, eachrepresent a (C₁-C₆)alkyl group, e.g. an ethyl group.

In the present invention by

pharmaceutically acceptable

is meant that which is useful for the preparation of a pharmaceuticalcomposition and is generally safe, non-toxic and neither biologicallynor otherwise undesirable and which is acceptable for veterinary use aswell as in human pharmaceutics.

By “pharmaceutically acceptable salts” of a compound is meant saltswhich are pharmaceutically acceptable as defined herein and which havethe desired pharmacological action of the parent compound. Such saltscomprise:

(1) pharmaceutically acceptable acid addition salts formed withpharmaceutically acceptable inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike; or formed with pharmaceutically acceptable organic acids such asacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid,citric acid, ethane-sulfonic acid, fumaric acid, glucoheptonic acid,gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonicacid, propionic acid, salicylic acid, succinic acid,dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, trifluoroacetic acid and the like; or

(2) the addition salts of pharmaceutically acceptable bases formed whenan acid proton contained in the parent compound is either replaced by ametal ion e.g. an alkaline metal ion, an alkaline-earth metal ion oraluminium ion; or coordinated with a pharmaceutically acceptable organicor inorganic base. Acceptable organic bases include diethanolamine,ethanolamine, N-methylglucamine, triethanolamine, tromethamine and thelike. Acceptable inorganic bases include aluminium hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Advantageously, it is an acid addition salt such as a hydrochloride orphosphate.

By “(C₁-C₆)alkyl” group in the meaning of the present invention is meanta linear or branched, saturated hydrocarbon chain having 1 to 6,preferably 1 to 4 carbon atoms. As examples mention can be made of thefollowing groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl.

By “alkaline metal alkoxide” in the meaning of the present invention ismeant a compound of formula AlkOM where M is an alkaline metal such assodium, potassium or lithium, and preferably sodium or potassium, andAlk is a (C₁-C₆)alkyl group such as defined above. In particular it maybe potassium or sodium tert-butoxide.

The reaction between the formula (II) and (III) compounds isadvantageously performed in the presence of a base. The base can beselected from among sodium hydride, an alkaline metal alkoxide (e.g.potassium or sodium tert-butoxide), 2,2,6,6-lithiumtetramethylpiperidide (LiTMP), lithium or potassium hexamethyldisilazide(LiHMDS or KHMDS), lithium diisopropylamide (LDA) or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The preferred base is sodiumhydride.

The reaction between the formula (II) and (III) compounds can beconducted in a solvent. Preferably, the reaction is conducted in a polaraprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide(DMSO), and ether solvents.

Advantageously, the solvent is an ether solvent such as tetrahydrofuran(THF), 2-methyl-tetrahydrofuran (MeTHF) or dimethyl ether (DME).

The ratio between the molar quantity of formula (II) aldehyde and themolar quantity of formula (III) phosphorus-containing derivative isadvantageously between 0.9:1 and 1:0.9, in particular between 0.95:1 and1:0.95, and is preferably about 1:1 (equimolar quantities of compounds(II) and (III)).

The reaction between the formula (II) and (III) compounds allows theenamine of following formula (IV) to be obtained:

which can then be hydrogenated to give the cinacalcet of formula (I),this optionally being converted to a pharmaceutically acceptable salt.

The reduction of the formula (IV) compound can be conducted in ahydrogen atmosphere in the presence of a hydrogenation catalyst inparticular a metal-based catalyst. For example, the metal may bepalladium, nickel or rhodium.

According to one preferred embodiment, reduction is conducted withpalladium on carbon (Pd/C) under a hydrogen atmosphere.

Reduction can be carried out in a solvent. Amongst suitable solvents,esters are cited such as a (C₁-C₆)alkyl acetates, in particular ethylacetate, (C₁-C₆)-alkanols (i.e. a compound of formula R—OH whereR=(C₁-C₆)alkyl) such as ethanol or methanol, and the mixtures thereof.The preferred solvent is ethanol.

The conditions under which reduction can be performed, such astemperature, amount of metal, hydrogen pressure, reaction time andconcentration can be determined by persons skilled in the art.

Advantageously, reduction is conducted at a temperature of between 20and 25° C. in the presence of a catalytic amount of the hydrogenationcatalyst, advantageously containing palladium such as Pd/C, and under ahydrogen pressure of 1 bar or higher, in particular between 1 and 5bars. The amount of catalyst is advantageously less than 10 mole %relative to the quantity in moles of the formula (IV) compound to behydrogenated.

The cinacalcet, after reduction of the formula (IV) enamine, can beisolated in its free form or in the form of a salt, using methods wellknown to skilled persons.

Preferably, the cinacalcet is obtained by precipitation in the form ofan acid salt that is pharmaceutically acceptable, such as the phosphatesalt or hydrochloride of cinacalcet. The cinacalcet salt thusprecipitated can be then converted to another cinacalcet salt which ispharmaceutically acceptable.

The phosphorus-containing derivative of formula (III) such as definedpreviously can be obtained by reaction of the phosphonate derivative offollowing formula (V):

where R₁ and R₂ are as previously defined,with (R)-(+)-1-(1-naphthyl)ethylamine of following formula (VI):

This reaction can be conducted in an ether solvent such astetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF) or dimethyl ether(DME).

The ratio between the molar quantity of phosphonate derivative offormula (V) and the molar quantity of the amine (VI) is advantageouslybetween 0.9:1 and 1:0.9, in particular between 0.95:1 and 1:0.95, and ispreferably about 1:1 (equimolar quantities of compounds (V) and (VI)).

In one preferred embodiment, the reaction between the formula (V)compound and the formula (IV) compound can be carried out at atemperature of between 0 and 20° C., advantageously at about 10° C.

The phosphonate derivative of formula (V) as defined previously can beobtained by hydrolysis of the following formula (VII) compound:

where R₁ and R₂ are as defined previously and R₃ and R₄, the same ordifferent, preferably the same, represent a (C₁-C₆)alkyl group, such asan ethyl group.

Preferably, the formula (VII) compound is diethyl2,2-diethoxyethylphosphonate.

This hydrolysis reaction is advantageously conducted in an acid medium,in particular in the presence of oxalic acid or hydrochloric acid.

The hydrolysis of the formula (VII) compound and the reaction of thephosphorus-containing derivative of formula (V) with the amine offormula (VI) can be conducted in one and the same reactor withoutisolating the synthesis intermediates.

The process of the invention therefore allows the obtaining ofcinacalcet or one of the pharmaceutically acceptable salts thereof inaccordance with the following reaction scheme:

where R₁, R₂, R₃ and R₄ are as previously defined.

This process has the advantage of being able to be performed in a fewsteps, using non-toxic reagents that are low cost and easilycommercially available.

The present invention also concerns(R)-(+)-1-(1-naphthylethylamino-vinyl-dialkyl-phosphonate of formula(III)

where R₁ and R₂ are as previously defined.

The present invention also concerns the use of a phosphorus-containingderivative of formula (III) as previously defined as synthesisintermediate in a process for preparing cinacalcet of formula (I) asdefined previously or one of the pharmaceutically acceptable saltsthereof, in particular cinacalcet hydrochloride.

The present invention also concerns a process for preparing thephosphorus-containing derivative of formula (III) as previously defined,comprising the reaction of the phosphonate derivative of followingformula (V):

where R₁ and R₂ are as previously defined,with (R)-(+)-1-(1-naphthyl)ethylamine of following formula (VI):

This reaction can be performed in an ether solvent such astetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF) or dimethyl ether(DME).

The ratio between the molar quantity of phosphonate derivative offormula (V) and the molar quantity of the amine (VI) is advantageouslybetween 0.9:1 and 1:0.9, in particular between 0.95:1 and 1:0.95, and ispreferably about 1:1 (equimolar quantities of compounds (V) and (VI)).

In one preferred embodiment, the reaction between the formula (V)compound and the formula (VI) compound can be conducted at a temperatureof between 0 and 20° C., advantageously at about 10° C.

The phosphonate derivative of formula (V) as defined above can beobtained by hydrolysis of the compound of following formula (VII):

where R₁ and R₂ are as previously defined and R₃ and R₄, the same ordifferent, preferably the same, represent a (C₁-C₆)alkyl group e.g. anethyl group.

Preferably the formula (VII) compound is diethyl2,2-diethoxyethylphosphonate.

This hydrolysis reaction is advantageously performed in an acid medium,in particular in the presence of oxalic acid or hydrochloric acid.

The hydrolysis of the formula (VII) compound and the reaction of thephosphonate derivative of formula (V) with the amine of formula (VI) canbe carried out in one and the same reactor without isolating thesynthesis intermediates.

The invention also concerns a process for obtaining and/or purifying acrystalline form of a pharmaceutically acceptable salt of cinacalcet,advantageously from the cinacalcet obtained with the process forpreparing cinacalcet according to the invention detailed in theforegoing, in particular a process for obtaining the phosphate salt ofcinacalcet or the hydrochloride of cinacalcet.

In a first embodiment, the crystalline form of the pharmaceuticallyacceptable salt of cinacalcet is obtained by neutralising a cinacalcetsalt followed by the addition of a pharmaceutically acceptable acid.According to this first embodiment, the cinacalcet hydrochloride can beprepared from the phosphate salt of cinacalcet.

In a second embodiment, the crystalline form of the pharmaceuticallyacceptable salt of cinacalcet is obtained by recrystallizing apharmaceutically acceptable salt of cinacalcet, such as thehydrochloride of cinacalcet.

In a third embodiment, the crystalline form of the pharmaceuticallyacceptable salt of cinacalcet is obtained by the addition of apharmaceutically acceptable acid to cinacalcet in the form of a freebase and recrystallization of the pharmaceutically acceptable salt ofcinacalcet obtained, such as the hydrochloride of cinacalcet.

The present invention therefore concerns a process for preparingcinacalcet hydrochloride, comprising the following successive steps:

-   -   (a) neutralising a phosphate salt of cinacalcet to give        cinacalcet in the form of a free base; and    -   (b) reacting the cinacalcet in the form of a free base as        obtained after previous step (a) with hydrochloric acid,        optionally in gaseous form (also called hydrogen chloride) to        give cinacalcet hydrochloride.

With said process it is possible to obtain cinacalcet hydrochloride inpurified form. The choice of the phosphate salt in this process isimportant since the use of other salts does not allow the hydrochlorideof cinacalcet to be obtained with such high degree of purity. Also, thedirect conversion of cinacalcet in free base form to cinacalcethydrochloride leads to a product which must be recrystallized severaltimes to obtain an acceptable degree of purity.

Step (a):

The neutralisation step is advantageously conducted in ethyl acetate assolvent.

A base such as sodium hydroxide, in particular in an aqueous solution,can be used to release cinacalcet in free base form from its phosphatesalt.

Neutralisation can therefore be carried out in a two-phase mixturecomprising an organic solvent such as ethyl acetate and an aqueoussolution containing a base such as an aqueous solution of sodiumhydroxide.

Once the cinacalcet is in free base form, the reaction mixture can bewashed with water, preferably demineralised water, to remove all themineral salts formed during this step.

If necessary, the amount of solvent used at this step, and moreparticularly of ethyl acetate, can be adjusted before performingfollowing step b) either by adding solvent, or by distilling a portionthereof to reduce the volume. The solvent could also be fully evaporatedand be replaced by another solvent. Advantageously, one portion of thesolvent is distilled before proceeding with step b) in the same solventwhich is preferably ethyl acetate.

Step (b):

This step can advantageously be conducted in ethyl acetate as solvent inwhich the cinacalcet in free base form is solubilised.

Hydrochloric acid in gaseous form or optionally in solution in ethylacetate is added to the reaction mixture to form cinacalcethydrochloride.

Once the cinacalcet hydrochloride is formed, it can be crystallized byadding an anti-solvent and/or by cooling the reaction mixture to atemperature of 30° C. or lower, preferably between 0 and 30° C., and inparticular at a temperature of about 0° C.

By “anti-solvent” in the meaning of the present invention is meant asolvent in which the cinacalcet hydrochloride is not soluble i.e. itssolubility in the said solvent is 1 g/L or lower. In particular it maybe heptane.

The cinacalcet hydrochloride can thus be obtained in crystalline andpurified form.

The crystalline form of cinacalcet hydrochloride obtained isparticularly in crystalline form I as described in patent application EP1 883 618, which is characterized by the following peaks obtained byX-ray powder diffraction: 13.9; 19.0; 21.3 and 25.5±0.2° 2θ.

The process for preparing cinacalcet hydrochloride may thereforecomprise the following successive steps:

-   -   (i) solubilising a phosphate salt of cinacalcet in ethyl        acetate;    -   (ii) adding a base such as sodium hydroxide, in particular in        aqueous solution, to form cinacalcet in the form of a free base;    -   (iii) washing the reaction medium with water, preferably        demineralised water;    -   (iv) optionally distilling a portion of the solvent;    -   (v) adding hydrochloric acid, in particular in gaseous form or        optionally in solution in ethyl acetate, to form cinacalcet        hydrochloride;    -   (vi) adding heptane;    -   (vii) cooling the reaction mixture to a temperature of 30° C. or        lower, preferably between 0 and 30° C., in particular at a        temperature of about 0° C.; and    -   (viii) recovering the crystallized cinacalcet hydrochloride thus        formed, in particular by filtration.

The present invention also concerns the phosphate salt of cinacalcet.

This phosphate salt of cinacalcet may be in polymorphous form,characterized by the following main peaks obtained by X-ray powderdiffraction:

d (Å) value Relative intensity (%) 19.86 100 9.95 12.9 6.62 36.7 6.2914.1 6.02 10.8 5.62 15.4 5.24 12.8 5.04 16.0 4.87 7.2 4.72 8.4 4.53 10.14.37 20.1 4.29 15.5 4.18 24.3 3.97 12.9 3.84 13.1 3.56 14.8 3.49 10.2

The present invention also concerns the phosphate salt of cinacalcet asmedicament, advantageously used in the treatment of secondaryhyperparathyroidism in patients suffering from chronic kidney failureand hypercalcaemia in patients suffering from cancer of the parathyroidgland.

The present invention also concerns the use of a phosphate salt ofcinacalcet to prepare a medicament particularly intended for thetreatment of secondary hyperparathyroidism in patients suffering fromchronic kidney failure and hypercalcaemia in patients suffering fromcancer of the parathyroid gland.

The present invention also concerns a therapeutic treatment method, moreparticular in order to treat secondary hyperparathyroidism in patientssuffering from chronic kidney failure and hypercalcaemia in patientssuffering from cancer of the parathyroid gland, comprising theadministration, to a person in need thereof, of a therapeuticallyefficient amount of cinacalcet phosphate salt.

The present invention also concerns a pharmaceutical compositioncomprising a cinacalcet phosphate salt and one or more pharmaceuticallyacceptable excipients. This pharmaceutical composition may be in anysuitable dosage form corresponding to a suitable route ofadministration. Preference is given to the oral route in capsule ortablet form.

The present invention will be better understood in the light of thefollowing non-limiting examples.

FIGURE

FIG. 1: Diagram of X-ray powder diffraction of the phosphate salt of(R)-(−)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalene-methanamine.

EXAMPLES

Cinacalcet hydrochloride was prepared in accordance with the process ofthe present invention as illustrated in the following scheme:

Diethyl formylmethylphosphonate (Step 1)

A 2-liter, four-necked flask equipped with a mechanical stirrer, anaddition funnel and a nitrogen inlet was charged with diethyl2,2-diethoxyethylphosphonate (150 g) and water (300 mL), and a slightstream of nitrogen was continuously passed through the system. Theresulting mixture was heated to 50° C. and hydrochloric acid (5.6 mL)was added. The mixture was then left under stirring for 4 hours afterwhich water was added and the mixture concentrated under reducedpressure. Sodium chloride was added to the resulting mixture which wasthen extracted with 4 portions of ethyl acetate. The combined organicphases were distilled under reduced pressure.

Diethyl 2-((R)-1-(1-naphthyl)ethylamino)vinylphosphonate (Step 2)

A 1-liter, four-necked flask equipped with a mechanical stirrer, anaddition funnel and a nitrogen inlet was charged with diethylformylmethylphosphonate (100 g) and ethanol (500 mL). Under a nitrogenatmosphere, the resulting mixture was cooled to 10° C. and(R)-1-(1-naphthyl)ethylamine (85.6 g) was added under stirring. Themixture was left under stirring for an additional hour. The solvent wasdistilled from this mixture under reduced pressure. The resultingresidue (180 g) was used in the next step without additionalpurification.

(R)-N-[3-[3-(Trifluoromethyl)phenyl]-2-propenylimino]-N-[1-(1-naphthyl)ethylamine] (Step 3)

A 1-liter, four-necked flask equipped with a mechanical stirrer, anaddition funnel and a nitrogen inlet was charged with sodium hydride(10.72 g) (60% dispersion in oil) and tetrahydrofuran (150 mL). Thesystem was placed under nitrogen and a solution of diethyl2-((R)-1-(1-naphthyl)ethylamino)vinylphosphonate (74.3 g.) in anhydroustetrahydrofuran (220 mL) was added. The mixture was left under stirringuntil completion of the reaction. A solution of3-trifluoromethylbenzaldehyde (38.8 g) was added and the mixture stirredfor an additional hour after which water was added to the mixture. Theaqueous phase was extracted with methyl butyl ether. The combinedorganic phases were washed with water and distilled under reducedpressure. The resulting residue (78.8 g) was used in the next stepwithout additional purification.

1^(st) Alternative(R)-(−)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanaminehydrochloride (Step 4)

The palladium catalyst (5% Pd/C—2.1 g) was added to a solution of(R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino]-N-[1-(1-naphthyl)ethylamine](44.2 g) in ethanol (440 mL) at ambient temperature under H₂ pressure (3bars). The mixture was stirred until completion of the reaction. Theheterogeneous mixture was filtered and a 20% solution of hydrochloricacid in isopropanol (27.4 g) was added at ambient temperature. Themixture was evaporated to dryness under reduced pressure.

Ethyl acetate was added and the mixture stirred. Heptane was then addedat ambient temperature and the mixture stirred. The solid obtained wasfiltered, washed and dried under reduced pressure to give 29.5 g ofproduct (yield: 60%; purity: 95.0%).

The product was recrystallized a second time following the sameprocedure (treatment with ethyl acetate followed by heptane) to give thedesired product with a yield of 80% and purity of 99.3%.

2^(nd) Alternative Phosphate salt of(R)-(−)-α-Methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanamine(Step 4)

In 1-liter hydrogenation apparatus equipped with a mechanical stirrer,the palladium catalyst (5% Pd/C—4.8 g) and a solution of(R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino]-N-[1-(1-naphthyl)ethylamine](82.2 g) in ethanol (500 mL) at ambient temperature and under H₂pressure (3 bars) were left under stirring for 4 hours. When thereaction was completed the heterogeneous mixture was filtered. Thesolvent was distilled from the mixture under reduced pressure. Ethylacetate was added. The solvents were distilled from the mixture underreduced pressure. Ethyl acetate and water were added at ambienttemperature followed by phosphoric acid (85% wt/wt-19.3 mL) Afterseeding (1% wt/wt), the mixture was stirred for 2 additional hours atambient temperature and cooled to 0° C. The mixture was stirred at 0° C.and the solid was filtered, washed with ethyl acetate and dried underreduced pressure to give 63.5 g of product (60%).

A 1-liter, four-necked flask equipped with a mechanical stirrer and anitrogen inlet was charged with the phosphate salt of(R)-(−)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanamine(100.0 g), ethyl acetate (500 mL) and water (100 mL). The resultingsuspension was heated to 70° C. and then cooled. The solid obtained wasfiltered, washed with ethyl acetate and dried under reduced pressure togive 95.0 g of product (95%).

The phosphate salt thus obtained was analysed under X-ray powderdiffraction (XRPD) under the following conditions:

-   -   Siemens diffractometer D5000    -   Copper anticathode, voltage 10 kV, intensity 40 mA    -   θ-θ assembly, fixed sample    -   Ambient temperature    -   Measurement range: 3° to 30°    -   Incrementation between each measurement: 0.04°    -   Measuring time pitch: 4 s    -   Fixed slits: 1.6 mm    -   No internal reference    -   Zero procedure with Siemens slits    -   Obtained experimental data processed using EVA software (v.        12.0)

The diagram of X-ray powder diffraction obtained is shown in FIG. 1. Themain peaks obtained in this diagram are characterized in the Tablebelow.

Angle 2θ (°) Value d (Å) Intensity (counts) Relative intensity (%) 4.44519.86 6655 100 8.880 9.95 856 12.9 13.356 6.62 2444 36.7 14.073 6.29 94114.1 14.714 6.02 716 10.8 15.765 5.62 1026 15.4 16.918 5.24 851 12.817.596 5.04 1068 16.0 18.200 4.87 476 7.2 18.787 4.72 561 8.4 19.6004.53 669 10.1 20.306 4.37 1338 20.1 20.699 4.29 1030 15.5 21.239 4.181619 24.3 22.393 3.97 857 12.9 23.166 3.84 871 13.1 25.024 3.56 986 14.825.508 3.49 680 10.2

(R)-(−)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanaminehydrochloride (Step 5)

A 1-liter, four-necked flask equipped with a mechanical stirrer, anaddition funnel and nitrogen inlet was charged with the phosphate saltof(R)-(−)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanamine(92 g) and ethyl acetate (368 mL) at ambient temperature. The system wasplaced under nitrogen and a solution of sodium hydroxide (20% NaOH-68mL) in water (278 mL) was added under stirring. The two-phase solutionwas left under stirring for 1 additional hour. The organic phase wasrecovered, washed with water, concentrated under reduced pressure andused in the remaining procedure. HCl gas (m g) was added to the solutionunder stirring and at ambient temperature but with temperature controlto ensure that the temperature of the solution did not exceed 25° C. Thesolution was cooled to 10° C. and stirred for 30 minutes.

Heptane was then added and the mixture was stirred. The resultingsuspension was stirred at 10° C. then cooled to 0° C. The solid obtainedwas filtered, washed with ethyl acetate/heptane mixture 50:50 v/v anddried under reduced pressure to give 75.6 g of the desired product(yield: 94%; purity: 99.9%).

The invention claimed is:
 1. A process for preparing cinacalcethydrochloride, comprising the following successive steps: (a)recrystallizing a phosphate salt of cinacalcet, (b) neutralising therecrystallized phosphate salt of cinacalcet obtained at preceding step(a) to give cinacalcet in the form of a free base; and (c) reacting thecinacalcet in free base form obtained at preceding step (b) withhydrochloric acid, optionally in gaseous form, to give cinacalcethydrochloride, wherein the recrystallized phosphate salt of cinacalcetis a polymorphous form characterized by the following main peaksobtained under X-ray powder diffraction: Value d (Å) Relative intensity(%) 19.86 100 9.95 12.9 6.62 36.7 6.29 14.1 6.02 10.8 5.62 15.4 5.2412.8 5.04 16.0 4.87 7.2 4.72 8.4 4.53 10.1 4.37 20.1 4.29 15.5 4.18 24.33.97 12.9 3.84 13.1 3.56 14.8 3.49 10.2.


2. The process according to claim 1, wherein the cinacalcethydrochloride is in crystalline form I.
 3. The process according toclaim 1, wherein the recrystallization step (a) is performed in amixture of ethyl acetate and water as solvent.
 4. The process accordingto claim 1, wherein the neutralisation step (b) is performed in ethylacetate as solvent.
 5. The process according to claim 1, wherein theneutralisation step (b) is performed in the presence of a base.
 6. Theprocess according to claim 5, wherein the base is sodium hydroxide. 7.The process according to claim 6, wherein the base is an aqueoussolution of sodium hydroxide.
 8. The process according to claim 1,wherein step (c) is performed in ethyl acetate as solvent.
 9. Theprocess according to claim 1, wherein step (c) is followed by acrystallization step.
 10. The process according to claim 9, wherein thecrystallization step is performed by adding an anti-solvent and/or bycooling the reaction mixture to a temperature of 30° C. or lower. 11.The process according to claim 10, wherein the temperature is comprisedbetween 0° C. and 30° C.
 12. The process according to claim 10, whereinthe anti-solvent is heptane.
 13. The process according to claim 1,comprising the following successive steps after the recrystallizationstep of the phosphate salt of cinacalcet: (i) solubilising therecrystallized phosphate salt of cinacalcet in ethyl acetate; (ii)adding a base to form cinacalcet in the form of a free base; (iii)washing the reaction medium with water; (iv) optionally distilling aportion of the solvent; (v) adding hydrochloric acid, in gaseous form orin solution in ethyl acetate, to form cinacalcet hydrochloride; (vi)adding heptane; (vii) cooling the reaction mixture to a temperature of30° C. or lower; and (viii) recovering the crystallized cinacalcethydrochloride thus formed.
 14. The process according to claim 13,wherein the water of step (iii) is demineralised water.
 15. The processaccording to claim 13, wherein step (viii) is performed by filtration.